1. Field of the Invention:
The present invention relates to a process for preparing derivatives of naphthazarin which are important materials for dyes and medicines. More particularly, it relates to a process for preparing a derivative of naphthazarin represented by the general formula (I) of: ##STR3## wherein X.sub.1 to X.sub.3 each stands for an atom or a group selected from the group consisting of hydrogen, a hydroxyl group, organic residues and halogens; and R.sub.1 to R.sub.6 each stands for an atom or a group selected from the group consisting of hydrogen and hydrocarbon groups.
2. Related Art Statement:
Derivatives of naphthazarin are important materials in the production of dyes and medicines. For example, the R-form isomer of 5,8-dihydroxy-2-(1-hydroxy-4-methyl-3-pentenyl)1,4-naphthalenedione represented by the following structural formula of: ##STR4## is referred to as Shikonin whereas the S-form isomer thereof is referred to as Alkannin, and both isomers have been used as dyes, medicines and starting materials therefor. On the other hand, the compounds represented by the general formula (I) are important as dyes, medicines and starting materials therefor. Particularly, 5,8-dihydroxy-2-(tetrahydro-5,5-dimethyl-2-furanyl)-1,4-naphthalenedione represented by the following structural formula of: ##STR5## may be prepared by processing the natural Shikonin and Alkannin with an acid catalyst, such as SnCl.sub.4, and usually referred to as Cycloshikonin and Cycloalkannin. It has been known in the art that these compounds exert excellent efficacies when used as anti-tumour agents, as reported, for example, by Chem. Pharm. Bull., 29, 116 to 122 (1981). It is also possible to synthesize a material for Shikonin and Alkannin through a method disclosed by the 50th Spring Meeting of the Japanese Chemical Society, preprint, 2R11 and by Japanese Patent Laid-Open Publication No. 175449/1984. However, such a synthesis has not been practised after all, or required very cumbersome processing steps for practical application.
The major reason therefor is that there has not been developed a practically applicable technology for introducing a substituting group having a carbon chain to the skeletal structure of naphthazarin. The two representative examples of the process for the synthesis of naphthazarin will be described hereinbelow. In the first process, an alkyl-1,5-dinitronaphthalene is treated with fuming sulfuric acid as represented by the following reaction formula of: ##STR6## wherein A.sub.1 to A.sub.4 each stands for hydrogen or an alkyl group.
In the second known process, a derivative of hydroquinone is reacted with a derivative of maleic anhydride through a Friedel-Crafts reaction as represented by the following reaction formula of: ##STR7## wherein A.sub.1 to A.sub.4 each stands for hydrogen or an alkyl group. However, these known processes has been used only in a very narrow application range, because of severe reaction conditions.
On the other hand, Ann. 540, 51 to 71 (1939) discloses a process for preparing derivatives of naphthazarin by reacting naphthazarin with aldehydes in the presence of hydrochloric acid as the catalyst. One example of such process may be represented by the following reaction formula of: ##STR8## However, a side chain substituting group including oxygen or like elements could not be introduced by the aforementioned prior art process.
Although J. Chem. Res. (S) 1977, 266 to 267 and J. Chem. Soc., Chem. Commun., 1983, 987 to 988 discloses processes for preparing derivatives of naphthazarin by which derivatives of naphthazarin having side chain substituting groups including oxygen are prepared. However, these known processes could not be practically industrialized because of complicated sequential steps with low yield.
Although Shikonin and Alkannin have great utilities, the utilization of these compounds was restricted in quantity, in addition to the problem of high cost, since the resources thereof were limited to natural resources. To overcome these problems, a few processes for preparing the same from starting materials other than natural resources have been developed. For example, J. Chem. Soc., Chem. Commun., 1983, 987 to 988 describes a chemical synthesis of a racemic isomer of Shikonin. However, this known process is not suited for industrialization, since it includes ten and several steps and large quntities of expensive starting materials are required for the practice thereof. It has been also known, for example by Japanese Patent Laid-Open Publication No. 16589/1985, a process for preparing Shikonin by the cultivation of plant cell. However, this process is not satisfactory in consideration of a large expense and low production rate and for the reason that a large expense is needed for the purification of the product.
Accordingly, there is a demand for a process for synthesizing a derivative of naphthazarin, which has substantial efficacy as a medicine of itself and may be used as a starting material for Shikonin and Alkannin, and for synthesizing Cycloshikonin and Cycloalkannin.